Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.230
Filtrar
1.
Int J Mol Sci ; 25(12)2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38928431

RESUMO

In orbital and ground-based experiments, it has been demonstrated that ionizing radiation (IR) can stimulate the locomotor and exploratory activity of rodents, but the underlying mechanism of this phenomenon remains undisclosed. Here, we studied the effect of combined IR (0.4 Gy γ-rays and 0.14 Gy carbon-12 nuclei) on the locomotor and exploratory activity of rats, and assessed the sensorimotor cortex volume by magnetic resonance imaging-based morphometry at 1 week and 7 months post-irradiation. The sensorimotor cortex tissues were processed to determine whether the behavioral and morphologic effects were associated with changes in neurotrophin content. The irradiated rats were characterized by increased locomotor and exploratory activity, as well as novelty-seeking behavior, at 3 days post-irradiation. At the same time, only unirradiated rats experienced a significant decrease in the sensorimotor cortex volume at 7 months. While there were no significant differences at 1 week, at 7 months, the irradiated rats were characterized by higher neurotrophin-3 and neurotrophin-4 content in the sensorimotor cortex. Thus, IR prevents the age-associated decrease in the sensorimotor cortex volume, which is associated with neurotrophic and neurogenic changes. Meanwhile, IR-induced increases in locomotor activity may be the cause of the observed changes.


Assuntos
Raios gama , Fatores de Crescimento Neural , Córtex Sensório-Motor , Animais , Córtex Sensório-Motor/metabolismo , Córtex Sensório-Motor/efeitos da radiação , Raios gama/efeitos adversos , Ratos , Masculino , Fatores de Crescimento Neural/metabolismo , Radiação Ionizante , Neurotrofina 3/metabolismo , Envelhecimento , Locomoção/efeitos da radiação , Imageamento por Ressonância Magnética
2.
PLoS Biol ; 22(6): e3002665, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38935589

RESUMO

Loss of synapses between spiral ganglion neurons and inner hair cells (IHC synaptopathy) leads to an auditory neuropathy called hidden hearing loss (HHL) characterized by normal auditory thresholds but reduced amplitude of sound-evoked auditory potentials. It has been proposed that synaptopathy and HHL result in poor performance in challenging hearing tasks despite a normal audiogram. However, this has only been tested in animals after exposure to noise or ototoxic drugs, which can cause deficits beyond synaptopathy. Furthermore, the impact of supernumerary synapses on auditory processing has not been evaluated. Here, we studied mice in which IHC synapse counts were increased or decreased by altering neurotrophin 3 (Ntf3) expression in IHC supporting cells. As we previously showed, postnatal Ntf3 knockdown or overexpression reduces or increases, respectively, IHC synapse density and suprathreshold amplitude of sound-evoked auditory potentials without changing cochlear thresholds. We now show that IHC synapse density does not influence the magnitude of the acoustic startle reflex or its prepulse inhibition. In contrast, gap-prepulse inhibition, a behavioral test for auditory temporal processing, is reduced or enhanced according to Ntf3 expression levels. These results indicate that IHC synaptopathy causes temporal processing deficits predicted in HHL. Furthermore, the improvement in temporal acuity achieved by increasing Ntf3 expression and synapse density suggests a therapeutic strategy for improving hearing in noise for individuals with synaptopathy of various etiologies.


Assuntos
Células Ciliadas Auditivas Internas , Neurotrofina 3 , Sinapses , Animais , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/patologia , Sinapses/metabolismo , Sinapses/fisiologia , Neurotrofina 3/metabolismo , Neurotrofina 3/genética , Camundongos , Limiar Auditivo , Potenciais Evocados Auditivos/fisiologia , Reflexo de Sobressalto/fisiologia , Percepção Auditiva/fisiologia , Gânglio Espiral da Cóclea/metabolismo , Feminino , Masculino , Perda Auditiva Oculta
3.
Med Sci (Basel) ; 12(2)2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38921685

RESUMO

Hemodialyzed patients have innate immunity activation and adaptive immunity senescence. Diabetes mellitus is a frequent cause for chronic kidney disease and systemic inflammation. We studied the immunological pattern (innate and acquired immunity) and the tissular regeneration capacity in two groups of hemodialyzed patients: one comprised of diabetics and the other of non-diabetics. For inflammation, the following serum markers were determined: interleukin 6 (IL-6), interleukin 1ß (IL-1ß), tumoral necrosis factor α (TNF-α), IL-6 soluble receptor (sIL-6R), NGAL (human neutrophil gelatinase-associated lipocalin), and interleukin 10 (IL-10). Serum tumoral necrosis factor ß (TNF-ß) was determined as a cellular immune response marker. Tissue regeneration capacity was studied using neurotrophin-3 (NT-3) and vascular endothelial growth factor ß (VEGF-ß) serum levels. The results showed important IL-6 and sIL-6R increases in both groups, especially in the diabetic patient group. IL-6 generates trans-signaling at the cellular level through sIL-6R, with proinflammatory and anti-regenerative effects, confirmed through a significant reduction in NT-3 and VEGF-ß. Our results suggest that the high serum level of IL-6 significantly influences IL-1ß, TNF-ß, NT-3, VEGF-ß, and IL-10 behavior. Our study is the first that we know of that investigates NT-3 in this patient category. Moreover, we investigated VEGF-ß and TNF-ß serum behavior, whereas most of the existing data cover only VEGF-α and TNF-α in hemodialyzed patients.


Assuntos
Interleucina-6 , Neurotrofina 3 , Diálise Renal , Humanos , Masculino , Interleucina-6/sangue , Feminino , Pessoa de Meia-Idade , Idoso , Fator de Necrose Tumoral alfa/sangue , Receptores de Interleucina-6 , Diabetes Mellitus , Lipocalina-2/sangue , Interleucina-1beta/sangue , Regeneração , Biomarcadores/sangue , Imunidade Inata , Inflamação , Adulto
4.
J Affect Disord ; 359: 327-332, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38795781

RESUMO

BACKGROUND: In the current study, it was aimed to evaluate neurotrophic factor levels and their relationship with executive functions in high-risk children and adolescents (high-risk group) whose parents were diagnosed with bipolar disorder (BD) but not affected by any psychiatric disease,and in order to determine possible vulnerability factors related to the disease. METHODS: The study sample consisted of 32 high-risk group and 34 healthy controls. The Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version-Turkish Adaptation (KSADS-PL-T), Stroop Test, Serial Digit Learning Test (SDLT) and Cancellation Test to evaluate executive functions were administered to all participants by the clinician.Serum levels of neurotrophic factors were measured using commercial enzyme linked immunosorbent assay kits. RESULTS: Serum BDNF, NT-3, NT-4 levels and SDLT scores were significantly lower in the high-risk group for BD compared to the healthy control group. A moderate negative correlation was found between BDNF levels and the Cancellation Test scores in the high-risk group. In addition to these results, the odds ratios of age, NT-4, SDLT scores for being in the risky group in terms of BD diagnosis were 1.26, 0.99 and 0.86 respectively. LIMITATIONS: This was a cross-sectional study. Causality between study results is therefore difficult to establish. The relatively small sample size of the study is another limitation. CONCLUSION: The results of the present study suggest that BDNF, NT-3, NT-4 may play a role in the physiopathology of BD and may be associated with impaired executive function areas such as attention and response inhibition in the high-risk group.


Assuntos
Transtorno Bipolar , Fator Neurotrófico Derivado do Encéfalo , Filho de Pais com Deficiência , Função Executiva , Testes Neuropsicológicos , Neurotrofina 3 , Humanos , Transtorno Bipolar/sangue , Transtorno Bipolar/fisiopatologia , Transtorno Bipolar/psicologia , Função Executiva/fisiologia , Masculino , Feminino , Fator Neurotrófico Derivado do Encéfalo/sangue , Estudos de Casos e Controles , Criança , Adolescente , Filho de Pais com Deficiência/psicologia , Neurotrofina 3/sangue , Pais/psicologia , Adulto , Fatores de Crescimento Neural
5.
Bull Exp Biol Med ; 176(5): 666-671, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38727956

RESUMO

This paper shows for the first time that co-transplantation of human olfactory ensheathing cells with neurotrophin-3 into spinal cord cysts is more effective for activation of remyelination than transplantation of cells with brain-derived neurotrophic factor and a combination of these two factors. The studied neurotrophic factors do not affect proliferation and migration of ensheathing cells in vitro. It can be concluded that the maximum improvement of motor function in rats receiving ensheathing cells with neurotrophin-3 is largely determined by activation of remyelination.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Neurotrofina 3 , Bulbo Olfatório , Remielinização , Animais , Ratos , Neurotrofina 3/metabolismo , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Remielinização/fisiologia , Bulbo Olfatório/citologia , Proliferação de Células , Medula Espinal/metabolismo , Bainha de Mielina/metabolismo , Bainha de Mielina/fisiologia , Células Cultivadas , Movimento Celular , Cistos/patologia , Feminino , Cistos do Sistema Nervoso Central/cirurgia , Cistos do Sistema Nervoso Central/patologia
6.
EMBO Rep ; 25(5): 2375-2390, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38594391

RESUMO

Cancer patients undergoing treatment with antineoplastic drugs often experience chemotherapy-induced neuropathic pain (CINP), and the therapeutic options for managing CINP are limited. Here, we show that systemic paclitaxel administration upregulates the expression of neurotrophin-3 (Nt3) mRNA and NT3 protein in the neurons of dorsal root ganglia (DRG), but not in the spinal cord. Blocking NT3 upregulation attenuates paclitaxel-induced mechanical, heat, and cold nociceptive hypersensitivities and spontaneous pain without altering acute pain and locomotor activity in male and female mice. Conversely, mimicking this increase produces enhanced responses to mechanical, heat, and cold stimuli and spontaneous pain in naive male and female mice. Mechanistically, NT3 triggers tropomyosin receptor kinase C (TrkC) activation and participates in the paclitaxel-induced increases of C-C chemokine ligand 2 (Ccl2) mRNA and CCL2 protein in the DRG. Given that CCL2 is an endogenous initiator of CINP and that Nt3 mRNA co-expresses with TrkC and Ccl2 mRNAs in DRG neurons, NT3 likely contributes to CINP through TrkC-mediated activation of the Ccl2 gene in DRG neurons. NT3 may be thus a potential target for CINP treatment.


Assuntos
Quimiocina CCL2 , Gânglios Espinais , Neuralgia , Neurônios , Neurotrofina 3 , Paclitaxel , Receptor trkC , Animais , Gânglios Espinais/metabolismo , Gânglios Espinais/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/genética , Paclitaxel/efeitos adversos , Paclitaxel/farmacologia , Neurotrofina 3/metabolismo , Neurotrofina 3/genética , Masculino , Camundongos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos , Feminino , Receptor trkC/metabolismo , Receptor trkC/genética , Antineoplásicos/efeitos adversos , RNA Mensageiro/metabolismo , RNA Mensageiro/genética
7.
J Speech Lang Hear Res ; 67(6): 1976-1983, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38687186

RESUMO

BACKGROUND: Age-related hearing loss (ARHL) is a general term used to describe the sensorineural type of hearing loss occurring in both ears in older adults. Neurotrophins are the most promising candidates for supporting the auditory nerve by increasing neuronal survival. This study aimed to help elucidate the pathophysiology of ARHL by determining whether any relationship exists between brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) levels in serum samples from patients diagnosed with ARHL. MATERIALS AND METHOD: Seventy-seven individuals, a study group of 41 patients diagnosed with ARHL, and a control group of 36 participants without hearing loss were evaluated. Serum samples were collected and used to measure serum BDNF and NT-3 levels with the new Nepenthe enzyme-linked immunosorbent assay method. RESULTS: Median pure-tone average results in the 2000, 4000, and 6000 Hz ranges were 52.5 (44.3-67.3) dB HL in the ARHL group and 13.5 (11.1-17.1) dB HL in the control group. The difference was statistically significant (p = .001). Although NT-3 and BDNF levels were both lower in ARHL patients than in participants without hearing loss, only the BDNF levels were significantly (p = .002) lower. Mean left and right ear word recognition scores were also lower in ARHL patients than in control groups. The ARHL group was further divided into two subgroups based on word recognition scores to evaluate significant differences in BDNF and NT-3 levels. No statistically significant difference was observed in BDNF and NT-3 levels between these subgroups. However, there was a significant difference in word recognition scores. CONCLUSIONS: Low BDNF levels in the ARHL group suggest that BDNF may play a role in the pathogenesis of ARHL. Patients with low (ARHL1) and high (ARHL2) word recognition scores were compared for the first time in the literature in terms of BDNF and NT-3 levels. However, the results were not statistically significant. This article is a preliminary study and was written to provide guidance for our next comprehensive project.


Assuntos
Limiar Auditivo , Fator Neurotrófico Derivado do Encéfalo , Neurotrofina 3 , Humanos , Fator Neurotrófico Derivado do Encéfalo/sangue , Neurotrofina 3/sangue , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Limiar Auditivo/fisiologia , Presbiacusia/sangue , Presbiacusia/fisiopatologia , Presbiacusia/diagnóstico , Audiometria de Tons Puros , Idoso de 80 Anos ou mais , Estudos de Casos e Controles
8.
Int J Mol Sci ; 25(5)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38473977

RESUMO

Specific subpopulations of neurons in nerve and sensory systems must be developed and maintained, and this is accomplished in significant part by neurotrophins (NTs) and the signaling receptors on which they act, called tyrosine protein kinase receptors (Trks). The neurotrophins-tyrosine protein kinase receptors (NTs/Trks) system is involved in sensory organ regulation, including the visual system. An NTs/Trks system alteration is associated with neurodegeneration related to aging and diseases, including retinal pathologies. An emergent model in the field of translational medicine, for instance, in aging study, is the annual killifish belonging to the Nothobranchius genus, thanks to its short lifespan. Members of this genus, such as Nothobranchius guentheri, and humans share a similar retinal stratigraphy. Nevertheless, according to the authors' knowledge, the occurrence and distribution of the NTs/Trks system in the retina of N. guentheri has never been investigated before. Therefore, the present study aimed to localize neurotrophin BDNF, NGF, and NT-3 and TrkA, TrkB, and TrkC receptors in the N. guentheri retina using the immunofluorescence method. The present investigation demonstrates, for the first time, the occurrence of the NTs/Trks system in N. guentheri retina and, consequently, the potential key role of these proteins in the biology and survival of the retinal cells.


Assuntos
Peixes Listrados , Fatores de Crescimento Neural , Receptores de Fator de Crescimento Neural , Humanos , Receptores de Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/metabolismo , Receptores Proteína Tirosina Quinases/fisiologia , Retina/metabolismo , Receptor trkA , Neurotrofina 3 , Fator Neurotrófico Derivado do Encéfalo
9.
Cell Mol Biol (Noisy-le-grand) ; 70(1): 56-61, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38372112

RESUMO

The present study aimed to study the repair effect of neurotrophic factor III (NT-3) on spinal injury model rats and its mechanism. Wistar rats with spinal injury were established by accelerated compression stroke after the operation and divided into control group, model group, and NT-3 intervention group. The motor function of rats in each group was evaluated at different postoperative time points (3, 7, 14 d). HE staining was used to detect the changes in tissue structure and morphology of the injured spinal column in each group. The changes of SOD, MDA and GSH in serum of rats were detected. The concentrations of inflammatory cytokines IL-1ß, IL-6, IL-17 and TNF-α in serum were detected by enzyme-linked immunosorbent assay (ELISA). Western blot was used to detect the expression changes of anti-apoptotic protein (Bcl-2) and pro-apoptotic protein (Bax) in injured spinal tissue of rats in each group. Compared with model group, motor function score of NT-3 intervention group increased gradually, and had statistical significance at 7 and 14 days (5.29±1.62 vs 9.33±2.16, 5.92±1.44 vs 14.56±2.45, T =7.386, 9.294, P =0.004, 0.000). The levels of SOD and GSH in serum of NT-3 intervention group were significantly increased (t=9.117, 12.207, P=0.000, 0.000), while the level of MDA was significantly decreased (t=5.089, P=0.011). Serum levels of inflammatory cytokines IL-1ß, IL-6, IL-17 and TNF-α in NT-3 intervention group were significantly decreased (T =6.157, 7.958, 6.339, 6.288, P=0.008, 0.005, 0.005, 0.007). In the NT-3 treatment group, Bax protein was significantly decreased (0.24±0.05 vs 0.89±0.12, T =8.579, P=0.001), and the relative expression of Bcl-2 protein was significantly increased (0.75±0.06 vs 0.13±0.05, T =9.367, P=0.001). Neurotrophic factor III can promote spinal injury repair in spinal injury model rats, and play a role by enhancing antioxidant stress ability, inhibiting inflammatory factors, promoting Bcl-2 and decreasing Bax expression.


Assuntos
Interleucina-17 , Neurotrofina 3 , Traumatismos da Coluna Vertebral , Animais , Ratos , Proteína X Associada a bcl-2 , Citocinas , Interleucina-1beta , Interleucina-6 , Fatores de Crescimento Neural , Proteínas Proto-Oncogênicas c-bcl-2 , Ratos Sprague-Dawley , Ratos Wistar , Superóxido Dismutase , Tromboplastina , Fator de Necrose Tumoral alfa/metabolismo
10.
Mol Psychiatry ; 29(4): 1192-1204, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38212372

RESUMO

At the center of the hippocampal tri-synaptic loop are synapses formed between mossy fiber (MF) terminals from granule cells in the dentate gyrus (DG) and proximal dendrites of CA3 pyramidal neurons. However, the molecular mechanism regulating the development and function of these synapses is poorly understood. In this study, we showed that neurotrophin-3 (NT3) was expressed in nearly all mature granule cells but not CA3 cells. We selectively deleted the NT3-encoding Ntf3 gene in the DG during the first two postnatal weeks to generate a Ntf3 conditional knockout (Ntf3-cKO). Ntf3-cKO mice of both sexes had normal hippocampal cytoarchitecture but displayed impairments in contextual memory, spatial reference memory, and nest building. Furthermore, male Ntf3-cKO mice exhibited anxiety-like behaviors, whereas female Ntf3-cKO showed some mild depressive symptoms. As MF-CA3 synapses are essential for encoding of contextual memory, we examined synaptic transmission at these synapses using ex vivo electrophysiological recordings. We found that Ntf3-cKO mice had impaired basal synaptic transmission due to deficits in excitatory postsynaptic currents mediated by AMPA receptors but normal presynaptic function and intrinsic excitability of CA3 pyramidal neurons. Consistent with this selective postsynaptic deficit, Ntf3-cKO mice had fewer and smaller thorny excrescences on proximal apical dendrites of CA3 neurons and lower GluR1 levels in the stratum lucidum area where MF-CA3 synapses reside but normal MF terminals, compared with control mice. Thus, our study indicates that NT3 expressed in the dentate gyrus is crucial for the postsynaptic structure and function of MF-CA3 synapses and hippocampal-dependent memory.


Assuntos
Região CA3 Hipocampal , Giro Denteado , Camundongos Knockout , Fibras Musgosas Hipocampais , Neurotrofina 3 , Sinapses , Animais , Giro Denteado/metabolismo , Fibras Musgosas Hipocampais/metabolismo , Sinapses/metabolismo , Camundongos , Neurotrofina 3/metabolismo , Neurotrofina 3/genética , Masculino , Feminino , Região CA3 Hipocampal/metabolismo , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Transmissão Sináptica/fisiologia , Cognição/fisiologia , Hipocampo/metabolismo , Camundongos Endogâmicos C57BL , Memória/fisiologia , Receptores de AMPA/metabolismo
11.
Mol Psychiatry ; 29(5): 1322-1337, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38233468

RESUMO

Fear-related pathologies are among the most prevalent psychiatric conditions, having inappropriate learned fear and resistance to extinction as cardinal features. Exposure therapy represents a promising therapeutic approach, the efficiency of which depends on inter-individual variation in fear extinction learning, which neurobiological basis is unknown. We characterized a model of extinction learning, whereby fear-conditioned mice were categorized as extinction (EXT)-success or EXT-failure, according to their inherent ability to extinguish fear. In the lateral amygdala, GluN2A-containing NMDAR are required for LTP and stabilization of fear memories, while GluN2B-containing NMDAR are required for LTD and fear extinction. EXT-success mice showed attenuated LTP, strong LTD and higher levels of synaptic GluN2B, while EXT-failure mice showed strong LTP, no LTD and higher levels of synaptic GluN2A. Neurotrophin 3 (NT3) infusion in the lateral amygdala was sufficient to rescue extinction deficits in EXT-failure mice. Mechanistically, activation of tropomyosin receptor kinase C (TrkC) with NT3 in EXT-failure slices attenuated lateral amygdala LTP, in a GluN2B-dependent manner. Conversely, blocking endogenous NT3-TrkC signaling with TrkC-Fc chimera in EXT-success slices strengthened lateral amygdala LTP. Our data support a key role for the NT3-TrkC system in inter-individual differences in fear extinction in rodents, through modulation of amygdalar NMDAR composition and synaptic plasticity.


Assuntos
Tonsila do Cerebelo , Extinção Psicológica , Medo , Individualidade , Camundongos Endogâmicos C57BL , Plasticidade Neuronal , Neurotrofina 3 , Receptor trkC , Receptores de N-Metil-D-Aspartato , Animais , Medo/fisiologia , Extinção Psicológica/fisiologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Masculino , Receptores de N-Metil-D-Aspartato/metabolismo , Receptor trkC/metabolismo , Neurotrofina 3/metabolismo , Potenciação de Longa Duração/fisiologia , Transdução de Sinais/fisiologia , Condicionamento Clássico/fisiologia
12.
Behav Brain Res ; 461: 114857, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38211776

RESUMO

Memory consolidation is an essential process of long-term memory formation. Neurotrophins have been suggested as key regulators of activity dependent changes in the synaptic efficacy and morphology, which are considered the downstream mechanisms of memory consolidation. The neurotrophin 3 (NT-3), a member of the neurotrophin family, and its high affinity receptor TrkC, are widely expressed in the insular cortex (IC), a region with a critical role in the consolidation of the conditioned taste aversion (CTA) paradigm, in which an animal associates a novel taste with nausea. Nevertheless, the role of this neurotrophin in the cognitive processes that the IC mediates remains unexamined. To answer whether NT-3 is involved in memory consolidation at the IC, adult male Wistar rats were administered with NT-3 or NT-3 in combination with the Trk receptors inhibitor K252a into the IC, immediately after CTA acquisition under two different conditions: a strong-CTA (0.2 M lithium chloride i.p.) or a weak-CTA (0.1 M lithium chloride i.p.). Our results show that NT-3 strengthens the memory trace of CTA, transforming a weak conditioning into a strong one, in a Trk-dependent manner. The present evidence suggests that NT-3 has a key role in the consolidation process of an aversive memory in a neocortical region.


Assuntos
Córtex Cerebral , Córtex Insular , Ratos , Animais , Masculino , Ratos Wistar , Paladar , Cloreto de Lítio/farmacologia , Neurotrofina 3 , Aprendizagem da Esquiva
13.
Neuro Endocrinol Lett ; 44(7): 439-443, 2023 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-37874553

RESUMO

BACKGROUND: Neurotrophins (NTs) encompass a group of closely associated proteins regulating various aspects of neuronal growth and survival. The potential association between work-related factors and the levels of circulating NTs has not been extensively examined. In this preliminary investigation, we evaluated plasma concentrations of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in a cohort of healthy individuals from three distinct professional categories, each with unique work environments and lifestyle factors. METHODS: The study involved 60 men from three professional fields: airline pilots, construction laborers, and fitness trainers (20 participants per category) recruited during routine occupational health appointments. Plasma levels of NTs were measured using commercially available immunoassays and compared in the three professional groups. RESULTS: Among the professions studied, fitness instructors displayed the highest concentrations of BDNF and NGF, with airline pilots ranking second, and construction workers showing the lowest levels. Significantly decreased NT-3 levels were observed in airline pilots compared to fitness instructors and construction workers, but no differences were found between the latter two occupations. NT-4 levels were similar across all three occupational groups. CONCLUSIONS: Our pilot results suggest that plasma concentrations of NTs, which are involved in various aspects of neuronal and cognitive functioning, may display significant differences among healthy individuals depending on their occupation. These observations warrant additional research to explore potential implications for the field of occupational medicine.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Indústria da Construção , Masculino , Humanos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator de Crescimento Neural/metabolismo , Neurotrofina 3 , Neurônios/metabolismo , Ocupações
14.
J Transl Med ; 21(1): 733, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37848983

RESUMO

BACKGROUND: Maintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms. METHODS: Western blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation. RESULTS: After peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway. CONCLUSION: NT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation.


Assuntos
Regeneração Nervosa , Neurotrofina 3 , Traumatismos dos Nervos Periféricos , Células de Schwann , Humanos , Axônios/metabolismo , Denervação , Sistema de Sinalização das MAP Quinases , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Neurotrofina 3/genética , Neurotrofina 3/metabolismo , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/terapia , Receptores Proteína Tirosina Quinases/metabolismo , Células de Schwann/metabolismo
15.
Int J Mol Sci ; 24(11)2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-37298444

RESUMO

Neurotrophins (NTFs) are structurally related neurotrophic factors essential for differentiation, survival, neurite outgrowth, and the plasticity of neurons. Abnormalities associated with neurotrophin-signaling (NTF-signaling) were associated with neuropathies, neurodegenerative disorders, and age-associated cognitive decline. Among the neurotrophins, brain-derived neurotrophic factor (BDNF) has the highest expression and is expressed in mammals by specific cells throughout the brain, with particularly high expression in the hippocampus and cerebral cortex. Whole genome sequencing efforts showed that NTF signaling evolved before the evolution of Vertebrates; thus, the shared ancestor of Protostomes, Cyclostomes, and Deuterostomes must have possessed a single ortholog of neurotrophins. After the first round of whole genome duplication that occurred in the last common ancestor of Vertebrates, the presence of two neurotrophins in Agnatha was hypothesized, while the monophyletic group of cartilaginous fishes, or Chondrichthyans, was situated immediately after the second whole genome duplication round that occurred in the last common ancestor of Gnathostomes. Chondrichthyans represent the outgroup of all other living jawed vertebrates (Gnathostomes) and the sister group of Osteichthyans (comprehensive of Actinopterygians and Sarcopterygians). We were able to first identify the second neurotrophin in Agnatha. Secondly, we expanded our analysis to include the Chondrichthyans, with their strategic phylogenetic position as the most basal extant Gnathostome taxon. Results from the phylogenetic analysis confirmed the presence of four neurotrophins in the Chondrichthyans, namely the orthologs of the four mammalian neurotrophins BDNF, NGF, NT-3, and NT-4. We then proceeded to study the expression of BDNF in the adult brain of the Chondrichthyan Scyliorhinus canicula. Our results showed that BDNF is highly expressed in the S. canicula brain and that its expression is highest in the Telencephalon, while the Mesencephalic and Diencephalic areas showed expression of BDNF in isolated and well-defined cell groups. NGF was expressed at much lower levels that could be detected by PCR but not by in situ hybridization. Our results warrant further investigations in Chondrichthyans to characterize the putative ancestral function of neurotrophins in Vertebrates.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Elasmobrânquios , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Filogenia , Vertebrados/genética , Vertebrados/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Peixes/metabolismo , Neurotrofina 3/metabolismo , Mamíferos/metabolismo
16.
Sci Signal ; 16(787): eadf6696, 2023 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-37253090

RESUMO

Organ size is maintained by the controlled proliferation of distinct cell populations. In the mouse liver, hepatocytes in the midlobular zone that are positive for cyclin D1 (CCND1) repopulate the parenchyma at a constant rate to preserve liver mass. Here, we investigated how hepatocyte proliferation is supported by hepatic stellate cells (HSCs), pericytes that are in close proximity to hepatocytes. We used T cells to ablate nearly all HSCs in the murine liver, enabling the unbiased characterization of HSC functions. In the normal liver, complete loss of HSCs persisted for up to 10 weeks and caused a gradual reduction in liver mass and in the number of CCND1+ hepatocytes. We identified neurotrophin-3 (Ntf-3) as an HSC-produced factor that induced the proliferation of midlobular hepatocytes through the activation of tropomyosin receptor kinase B (TrkB). Treating HSC-depleted mice with Ntf-3 restored CCND1+ hepatocytes in the midlobular region and increased liver mass. These findings establish that HSCs form the mitogenic niche for midlobular hepatocytes and identify Ntf-3 as a hepatocyte growth factor.


Assuntos
Células Estreladas do Fígado , Fígado , Neurotrofina 3 , Animais , Camundongos , Proliferação de Células , Células Estreladas do Fígado/metabolismo , Hepatócitos/metabolismo , Fígado/metabolismo , Neurotrofina 3/metabolismo
17.
Sci Rep ; 13(1): 4571, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36941445

RESUMO

The purpose of this study was to determine whether altered serum and/or muscle concentrations of brain-derived neurotrophic factor (BDNF) can modify the electrophysiological properties of spinal motoneurons (MNs). This study was conducted in wild-type and Bdnf heterozygous knockout rats (HET, SD-BDNF). Rats were divided into four groups: control, knockout, control trained, and knockout trained. The latter two groups underwent moderate-intensity endurance training to increase BDNF levels in serum and/or hindlimb muscles. BDNF and other neurotrophic factors (NFs), including glial cell-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), and neurotrophin-4 (NT-4) were assessed in serum and three hindlimb muscles: the tibialis anterior (TA), medial gastrocnemius (MG), and soleus (Sol). The concentrations of tropomyosin kinase receptor B (Trk-B), interleukin-15 (IL-15), and myoglobin (MYO/MB) were also evaluated in these muscles. The electrophysiological properties of lumbar MNs were studied in vivo using whole-cell current-clamp recordings. Bdnf knockout rats had reduced levels of all studied NFs in serum but not in hindlimb muscles. Interestingly, decreased serum NF levels did not influence the electrophysiological properties of spinal MNs. Additionally, endurance training did not change the serum concentrations of any of the NFs tested but significantly increased BDNF and GDNF levels in the TA and MG muscles in both trained groups. Furthermore, the excitability of fast MNs was reduced in both groups of trained rats. Thus, changes in muscle (but not serum) concentrations of BDNF and GDNF may be critical factors that modify the excitability of spinal MNs after intense physical activity.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Neurotrofina 3/metabolismo , Neurônios Motores/metabolismo , Músculo Esquelético/metabolismo
18.
Int J Mol Sci ; 24(3)2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36768339

RESUMO

Neurotrophins promote neurite outgrowth of auditory neurons and may help closing the gap to cochlear implant (CI) electrodes to enhance electrical hearing. The best concentrations and mix of neurotrophins for this nerve regrowth are unknown. Whether electrical stimulation (ES) during outgrowth is beneficial or may direct axons is another open question. Auditory neuron explant cultures of distinct cochlear turns of 6-7 days old mice were cultured for four days. We tested different concentrations and combinations of BDNF and NT-3 and quantified the numbers and lengths of neurites with an advanced automated analysis. A custom-made 24-well electrical stimulator based on two bulk CIs served to test different ES strategies. Quantification of receptors trkB, trkC, p75NTR, and histological analysis helped to analyze effects. We found 25 ng/mL BDNF to perform best, especially in basal neurons, a negative influence of NT-3 in combined BDNF/NT-3 scenarios, and tonotopic changes in trk and p75NTR receptor stainings. ES largely impeded neurite outgrowth and glia ensheathment in an amplitude-dependent way. Apical neurons showed slight benefits in neurite numbers and length with ES at 10 and 500 µA. We recommend BDNF as a potent drug to enhance the man-machine interface, but CIs should be better activated after nerve regrowth.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Implantes Cocleares , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Receptores de Fator de Crescimento Neural , Neuritos , Nervo Coclear , Estimulação Elétrica , Crescimento Neuronal , Neurotrofina 3
19.
J Neurosci ; 43(9): 1492-1508, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36653191

RESUMO

NG2 is a structurally unique transmembrane chondroitin sulfate proteoglycan (CSPG). Its role in damaged spinal cord is dual. NG2 is considered one of key inhibitory factors restricting axonal growth following spinal injury. Additionally, we have recently detected its novel function as a blocker of axonal conduction. Some studies, however, indicate the importance of NG2 presence in the formation of synaptic contacts. We hypothesized that the optimal treatment would be neutralization of inhibitory functions of NG2 without its physical removal. Acute intraspinal injections of anti-NG2 monoclonal antibodies reportedly prevented an acute block of axonal conduction by exogenous NG2. For prolonged delivery of NG2 function neutralizing antibody, we have developed a novel gene therapy: adeno-associated vector (AAV) construct expressing recombinant single-chain variable fragment anti-NG2 antibody (AAV-NG2Ab). We examined effects of AAV-NG2Ab alone or in combination with neurotrophin NT-3 in adult female rats with thoracic T10 contusion injuries. A battery of behavioral tests was used to evaluate locomotor function. In vivo single-cell electrophysiology was used to evaluate synaptic transmission. Lower urinary tract function was assessed during the survival period using metabolic chambers. Terminal cystometry, with acquisition of external urethral sphincter activity and bladder pressure, was used to evaluate bladder function. Both the AAV-NG2Ab and AAV-NG2Ab combined with AAV-NT3 treatment groups demonstrated significant improvements in transmission, locomotion, and bladder function compared with the control (AAV-GFP) group. These functional improvements associated with improved remyelination and plasticity of 5-HT fibers. The best results were observed in the group that received combinational AAV-NG2Ab+AAV-NT3 treatment.SIGNIFICANCE STATEMENT We recently demonstrated beneficial, but transient, effects of neutralization of the NG2 proteoglycan using monoclonal antibodies delivered intrathecally via osmotic mini-pumps after spinal cord injury. Currently, we have developed a novel gene therapy tool for prolonged and clinically relevant delivery of a recombinant single-chain variable fragment anti-NG2 antibody: AAV-rh10 serotype expressing scFv-NG2 (AAV-NG2Ab). Here, we examined effects of AAV-NG2Ab combined with transgene delivery of Neurotrophin-3 (AAV-NT3) in adult rats with thoracic contusion injuries. The AAV-NG2Ab and AAV-NG2Ab+AAV-NT3 treatment groups demonstrated significant improvements of locomotor function and lower urinary tract function. Beneficial effects of this novel gene therapy on locomotion and bladder function associated with improved transmission to motoneurons and plasticity of axons in damaged spinal cord.


Assuntos
Contusões , Anticorpos de Cadeia Única , Traumatismos da Medula Espinal , Sistema Urinário , Animais , Feminino , Ratos , Contusões/terapia , Locomoção , Fatores de Crescimento Neural , Recuperação de Função Fisiológica/genética , Medula Espinal , Transmissão Sináptica , Neurotrofina 3
20.
Biol Trace Elem Res ; 201(2): 689-697, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35349008

RESUMO

BACKGROUND: Epilepsy is one of the most common neurological disorders, and it places a significant economic strain on the healthcare system around the world. Although the exact mechanism of epilepsy has yet to be illustrated, various pathogenic cascades involving neurotransmitters and trace elements have been reported. We aimed to investigate the serum levels of growth-associated protein-43 (GAP-43) and neurotrophin-3 (NT-3) among cohort of Egyptian children with epilepsy and correlate these biomarkers with their zinc levels. METHODS: This case-control study included 50 pediatric patients with epilepsy who were comparable with 50 controls. Neurological assessment and electroencephalogram (EEG) were done to all included children. Biochemical measurements of serum GAP-43 and NT-3 using enzyme linked immunosorbent assays (ELISA), and total antioxidant capacity (TAC) and zinc using colorimetric assays, were performed to all participants. RESULTS: There was significantly frequent positive parental consanguinity among cases with significantly frequent generalized onset seizures (94%) than simple partial seizure (6%). There were significantly lower serum GAP-43 and zinc levels with significantly higher TAC among cases vs. the controls, p˂0.05 for all. There was no significant difference in the serum levels of NT-3 among epileptic children vs. the controls, p = 0.269. Serum Zn was positively correlated with GAP-43 level among epileptic children (r = 0.381, p = 0.006). Serum GAP-43 in diagnosing childhood epilepsy at cut-off point ≤ 0.6 ng/mL showed 78% sensitivity, 62% specificity, positive predictive value (PPV) = 50.6%, negative predictive value (NPP) = 84.9% with AUC = 0.574. CONCLUSION: GAP-43 can be considered a sensitive good negative biomarker in childhood epilepsy which correlated positively with the zinc status.


Assuntos
Epilepsia , Proteína GAP-43 , Neurotrofina 3 , Zinco , Criança , Humanos , Estudos de Casos e Controles , Epilepsia/diagnóstico , Proteína GAP-43/sangue , Oligoelementos , Neurotrofina 3/sangue , Egito
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...